Setting: Secondary referrals at Department of Otolaryngology, Glasgow Royal Infirmary.

Location: Glasgow, UK.

Trial in other CSOM reviews: systemic versus topical treatments.

Allocation concealment

B

Study

Clayton 1990

Methods

RCT

Participants

See Table 03

139 randomised ears (20 CSOM); 102 ears (15 CSOM) analysed. Participants with otorrhoea caused by otitis externa and mastoid cavities were also included in the trial. Randomisation was not described as stratified by diagnosis, so all cases are included in this review (although results were presented separately in the trial publication).

Excluded participants who failed to attend clinics or failed to comply with treatment.

* Outcomes not included in this review were also assessed - see table 05 *

Notes

Setting: ENT Department, Bradford Royal Infirmary.

Location: UK.

Allocation concealment

A

Study

Fradis 1997

Methods

RCT

Participants

See Table 03

51 participants (aged 18 to 73), contributing 60 ears with purulent disease were randomised; 54 ears analysed.3 ears had surgical perforations and no perforation could be seen in 8 ears due to granulation tissue - not analysed separately.

11 participants (12 ears; 7 CSOM ears) then crossed over to the alternative treatment. Unless otherwise indicated, only numbers before crossover have been used for this review.

Participants with otorrhoea from post-operative or mastoid cavity infections, subacute otitis media, and otitis externa were also included in the trial. Type of infection was the principal criteria for randomisation (minimisation), but it is unclear whether this relates to diagnosis (balanced across treatments) or bacteriology, so all cases are included in this review (although results were presented separately in the trial publication).

Participants with otorrhoea from post-operative or mastoid cavity infections, subacute otitis media, and otitis externa were also included in the trial. Randomisation was not described as stratified by diagnosis, so all cases are included in this review (although results were presented separately in the trial publication).

ALLOCATIONNot a randomised controlled trial - topical or systemic gentamicin administered to a series of unselected participants, with choice of allocation usually based on in vitro sensitivity tests.

Fliss 1990

INTERVENTIONNo participants received topical antimicrobial agents (allocated 1 of 2 different systemic antibiotics or no treatment).

Fontanel 1998

ALLOCATIONNot a randomised controlled trial.

Foshee 1992

PARTICIPANTSTwo trials reported in this one article. In both trials, participants had acute otitis media with effusion, not chronic suppurative otitis media.INTERVENTIONParticipants were not allocated topical antibiotics in either trial (oral antibiotics only).

Garcia-Rodriguez 93a

ALLOCATIONParticipants divided into two treatment groups (0.2% or 0.5% ciprofloxacin drops) but allocation was not described as randomised.

Garcia-Rodriguez 93b

ALLOCATIONParticipants divided into three treatment groups (oral and/or topical ciprofloxacin) but allocation was not described as randomised.INTERVENTIONOnly 1 group received topical antibiotic without systemic treatment.

ALLOCATIONTreatment allocation not described as random (cases were selected at random, but unclear how control group was selected).INTERVENTIONTrial tests a mucolytic agent, Acetylcysteine; no comparisons with topical antibiotics or topical versus systemic treatment.

INTERVENTIONMethod of treatment delivery and aspiration daily or once only are compared, and not the actual treatment: daily topical ciprofloxacin following aspiration administered by clinic personnel at the clinic, versus topical quinolone self-administered at home after the first treatment with aspiration at the clinic only.

Study 2 of 2:ALLOCATIONTreatment allocation not described as randomised.INTERVENTIONBacterial study of oral amoxyclav compared to alternative oral treatments for a range of inflammatory ENT infections.

Lancaster 1999

ALLOCATIONNot a randomised controlled trial (all participants received topical gentamicin with comparisons made between their diseased and non-diseased ears before and after treatment).

Lancaster 2003

ALLOCATIONParticipants received antibiotic drops or spray, but treatment allocation was not described as randomised.

ALLOCATIONParticipants were divided into two groups (receiving oral or topical antibiotic), but not described as randomised.INTERVENTIONOnly one group received topical antibiotic without systemic treatment.

Treatment allocation described as random, using random numbered list kept by the pharmacist, who dispensed the medication, but method of sequence code generation was not stated.

The choice of antibiotic depended on sensitivity results of ear discharge isolates.

Participants with Pseudomonas species isolated were randomised to topical antibiotics or antiseptics only - not to oral antibiotics due to resistance.

Did not discuss whether randomisation was stratified by the different diagnostic groups (and results not reported separately in trial report).

Unclear

Medication was supplied in the clinic by the pharmacist using the random numbered list, after eligibility assessments by the clinicians, who were blinded (except for antiseptic). Whether treatment was concealed from the pharmacist is not discussed.

Unclear Baseline characteristics (including the distribution of participants with and without modified radical mastoidectomy) not reported.

Single blind

Allocation was kept blinded from the clinicians, with the necessary exception of antiseptic, given by the otologist after aural toilet.

Inadequate

32% dropout: 24/75 participants were defaulters or non-compliers (ie used <75% of the medication). (Numbers excluded not given by treatment group or diagnosis).

Results given for the 51 participants who complied with treatment only (38 on topical antibiotics or antiseptics, included in this review).

Clayton 1990

Unclear

Treatment allocation described as random, with medication codes; but no further details of sequence generation method were given.

Did not discuss whether randomisation was stratified by the different diagnostic groups - therefore included all participants in this review.

Adequate

Patients were randomly allocated treatment in a double-blind fashion.

Medication codes were known only by the pharmacy.

No

The following imbalances were reported for analysed participants, after exclusions (due to failure to attend clinic or comply with treatment; exclusions were not reported by treatment group):

Significant bias (P=0.0002) for more mildest disease score (score 1) in the antiseptic group (1/60) than antibiotic (11/42) - scores not presented by diagnosis;

More ears with otitis externa (significant) and central perforations (not reported as significant) were analysed in the antibiotic group than antiseptic (see Table 02 for numbers).

Double blinded

Inadequate

Dropout rates (numbers of randomised ears that were excluded; not reported by treatment group):

Used Taves' method of minimisation, with type of infection as the principal criteria.

Minimisation is an alternative method to stratified randomisation for treatment allocation. It is sometimes recommended for small sample sizes, and can incorporate more prognostic factors (Scott 2002).

Unclear whether 'type of infection' relates to diagnosis or bacteriology - therefore included all participants in this review.

Unclear

Allocation concealment not mentioned, except that solutions were called 'A' (TSP) and 'B' (gentamicin) (trial was described as double blind).

Taves' minimisation approach can lead to predictability of treatment allocation in some situations.

Yes

Ears were balanced accross treatments for diagnosis (equal numbers per treatment) before and after crossover.

Balanced for age, sex, and diagnosis, with no great differences betwen the seriousness of infections in the two groups, according to the trialists. These results are for all ears including crossed-over cases, so some participants are counted twice (bilateral disease or crossover) and 1 was counted 4 times (bilateral disease and crossed over).

But there was more bilateral disease in the TSP group (7/43 participants = 16.3%) than on gentamicin (2/48=4.2%), for all participants before crossover.

Double-blind

The solutions were called 'A' (TSP) and 'B' (gentamicin) to conserve the double blind.

The treatment provider/outcome assessor was blinded until after the analysis of the results. Participants were also blinded.

Unclear

No withdrawal was reported - numbers analysed are the same as the reported numbers eligible for the study.

But participants unable to continue the proposed length of treatment or return for follow-up visits were excluded.

Appears to be only per protocol population reported and analysed; number of excluded noncompliers was not reported.

Gyde 1981

Unclear

Participants were randomly assigned to one treatment group using coded medications, but method of generation of random codes was not described.

Did not discuss whether randomisation was stratified by the different diagnostic groups - therefore included all participants in this review.

Adequate

Medications were coded and identically labelled, and used sequentially starting with the lowest number; no number was skipped or used more than once.

Mostly

Comparable across treatment groups (for ears) for diagnosis.

Overall results for age and bacteria were also comparable (not broken down by diagnosis).

But there was a slightly higher proportion of males in the TP group (17/33 ears, 51.5%) than the TSP group (25/35 ears, 71.4%).

Double blind

Unclear

No withdrawal was reported - number analysed is the same as the reported number of ears eligible for the study.

But participants unable to continue the proposed length of treatment or return for follow-up visits were excluded.

Appears to be only per protocol population reported and analysed; number of excluded noncompliers was not reported.

Jaya 2003

Unclear

Treatment allocation described as random, with coded bottles, but method of generation of random codes was not described.

Adequate

Both drugs were coloured identically and were dispensed in identical bottles, labelled with code numbers only - given to participants after baseline assessments.

Mostly

Comparable for a range of demographic and disease related (prognostic) factors, except more participants receiving PVP-I were male (10/19, 52.6%), than on ciprofloxacin (4/21, or 19.0%).

Other prognostic criteria were assessed and found to have no significant effect on the outcomes for the compared treatments.

Not clear how many people were originally randomised into the trial. (No exclusion was reported.)

Macfadyen 2005

Adequate

Treatment was prepared according to computer generated block randomisation schedule, stratified by school.

Adequate.

Treatment was identical in appearance, and identically labeled and packaged in treatment boxes, identifiable by school name and trial number only. Treatment packs remained sealed until sequentially allocated to a child.

Yes

Comparable for age*, sex, duration of current episode*, proportion of bilateral cases*, size of perforation*, cause of current episode, whether previous ear treatment had ever been used, and hearing level.

* Logistic regression adjusting for these factors did not significantly alter the treatment effect.

Double blind

Participants, care-givers, and outcome assessors remained blind to the treatment allocated throughout the study.

Adequate

Number with missing data and so excluded from analysis for resolution of discharge at four weeks: 33/427 (7.7%) total;20/216 (9%) ciprofloxacin;13/211 (6%) boric acid.

Some of these were due to missing data for participants seen at that visit.

The rest were due to withdrawals or lost to follow up:25/427 (5.9%) total; 16/216 (7.4%) ciprofloxacin (15 lost to follow-up; 1 consent withdrawn); 9/211 (4.3%) boric acid (all lost to follow-up).

All analyses followed the Intention To Treat principle.

Tutkun 1995

Unclear

Participants were randomly divided into two groups but randomisation method was not stated.

Unclear

Allocation concealment not reported - nor was blinding.

Unclear?

Only reported baseline data for bacteriology - comparable apart from "normal flora" isolated in the ciprofloxacin group only (4 cases; excluded from hearing analyses in Ozagar 1997.

Unclear

Blinding not mentioned.

Unclear

It is not clear how many people were originally randomised into the trial - an unreported number of non-compliers (participants who did not use the topical solutions regularly and those who had taken any other medication during the study period) were excluded from study.

Exclusion criteria - treatment related:1) Known allergy to any components of the trial drugs.2) Use of high doses of local (topical) corticosteroid preparations.3) Previous use of ototoxic drug therapy.4) Use of general or topical antibiotics within two weeks before study entry.5) Unable to continue the proposed length of treatment or return for follow-up visits due to distance or inconvenience.

13/68 ears were paediatric (< 12 years old), 12/68 ears were geriatric (> 70 years old).Concurrent medications, such as analgesics and decongestants etc were allowed.

Exclusion criteria - treatment related:1) History of sensitivity to any components of the trial drugs.2) Use of extensive ototopical corticosteroid preparations within the past four weeks.3) Previous use of ototoxic drug therapy.4) Use of oral or parenteral antibiotics within two weeks before study entry.5) Unable to continue the proposed length of treatment or return for follow-up visits due to distance or inconvenience.

Inclusion criteria - other:1) School children (enrolled at Kisumu rural primary schools visited)2) Age five years or older (range was 4 to 19 years)3) Informed consent (parental consent for affected children; school staff and parent-teacher-association representatives consented to school participation).

Exclusion criteria - treatment related:1) Treated for ear infection or received antibiotics for any other disorder in the previous 2 weeks 2) Allergy to study drugs.

1b) Sensitivity of pre and post (24 hrs)-treatment bacteria to ciprofloxacin and tobramycin.

Ears

Gyde 1978

1) Ears with clinical cure or failure at 6 months:

Success: dry ear within 3 weeks of treatment, or sufficiently improved after 3 weeks that 3 weeks further therapy allowed the discharge to stop; with negative post-treatment culture; and no return of the same strain of causative organism within 6 months of stopping treatment.

Failure: evidence of exudate after 3 weeks, with a positive culture and little hope of further improvement. Failures at 6 months were allocated the alternative treatment, and followed-up for 6 months as before.

Results at 6 months, before crossover, have been taken for this review.

1) Hearing assessment in 50 participants: pre and post-treatment audiometry, with a follow-up audiogram by a certified audiologist.

Results for average hearing loss before and after treatment, average improvement, and variation in improvement, are reported for each treatment group and treatment + 'intervention' (unclear what this is - possibly surgery).

Post-treatment observations were 3 to 12 months after medical treatment or surgery, to detect any delayed ototoxicity.

Audiometry (or an assessment of impedence, or both) assessed for a subset of 50 subjects only.

Results were not reported separately by diagnosis; all analysed cases are included in this review.

1) Ototoxicity: pre and post-treatment audiometry, with a follow-up audiogram by a certified audiologist. Post-treatment observations were 3 to 12 months after medical treatment or surgery, to detect any delayed ototoxicity.

Audiometry (or an assessment of impedence, or both) assessed for a subset of 50 subjects only (not reported separately by diagnosis).

2) Adverse reactions: open-ended question with further questioning for intensity of reaction. No specific or suggestive questions were asked.

Unilateral cases: 1 single reading taken from the diseased ear;Bilateral disease: calculated average across both ears.

Presented results for mean improvements in hearing threshold, and the difference in improvement between treatments, controlling for baseline threshold with analysis of covariance (ANCOVA). Adding background noise as an additional covariate did not change the conclusions.

Also described hearing impairment levels using WHO classifications; considered changes between levels using Fishers exact test.

The results of audiometry (tested on 50 subjects, 3 to 12 months after treatment or additional surgery) showed no signs of ototoxicity either immediatly after the treatment , or later on, for either treatments (see separate table for results).

The majority of the participants tested showed an improvement of the auditory acuteness, and hearing results remained stable in all cases examined during the 3 to12 month post-observation period.

There were no unfavourable reactions nor side effects following the administration of either treatment.

The participants did not complain about pain, itching or of burn.

The treatment did not cause allergic reactions not excessive fungal growth.

Howard JE, Nelson JD, Clahsen J, Jackson LH. Otitis media of infancy and early childhood. A double-blind study of four treatment regimens. American Journal of Diseases of Children 1976 Sep;130(9):965-70.

The Uppsala Monitoring Centre. http://www.who-umc.org/ viewed 17 June 2003. The UMC - the Global Intelligence Network for Benefits and Risks in Medicinal Products. WHO Collaborating Centre for International Drug Monitoring. 2003.

The International Bank for Reconstruction and Development / The World Bank. Appendix B. The global burden of disease, 1990. World development Report 1993: Investing in Health. Oxford: Oxford University Press, 1993:213-25.